The efficacy of interventions to prevent type 2 diabetes among women with recent gestational diabetes mellitus—A living systematic review and meta‐analysis

Abstract Background While previously considered a transient condition, with no lasting adverse impact, gestational diabetes mellitus (GDM) is now a well‐established risk factor for developing type 2 diabetes mellitus (T2DM). The risk of developing T2DM appears to be particularly high in the first few years after childbirth, providing a compelling case for early intervention. This review provides an up‐to‐date systematic review and meta‐analysis to assess the effectiveness of interventions to reduce incidence of T2DM in women with a recent history of GDM. Methods The search was conducted on October 20, 2023 with an annual surveillance planned for the next 5 years to maintain a living systematic review. The inclusion criteria were randomized controlled trials of any type in women within 5 years of GDM‐complicated pregnancy that reported outcomes of T2DM diagnosis or measures of dysglycemia with a follow‐up of at least 12 months. Results Seventeen studies met our inclusion criteria and have been included in this review. There were 3 pharmacological and 14 lifestyle interventions. Intervention was not associated with significant reduction in the primary outcome of T2DM (risk ratio, 0.78; 95% confidence interval [CI]: 0.43–1.41; p = 0.41; I 2 = 79%) compared with the control group (placebo or usual care). However, meta‐analysis of the four studies reporting hazard ratios suggested a reduction in diabetes incidence (hazard ratio, 0.68; 95% CI: 0.48–0.97; p = 0.03; I 2 = 31%). Conclusion This review provides equivocal evidence about the efficacy of interventions to reduce the risk of T2DM in women within 5 years of GDM‐complicated pregnancy and highlights the need for further studies, including pharmacotherapy.


K E Y W O R D S
impaired glucose tolerance, postpartum, prevention

| INTRODUCTION
Diabetes is a leading and growing cause of morbidity and mortality in adults worldwide. 1An estimated 537 million adults live with diabetes, with this condition accounting for approximately 6.7 million deaths in 2021. 2 Importantly, diabetes-related disability adjusted life-year loss, contributing to the largest rise in global burden among noncommunicable diseases, increasing by 148% from 1990 to 2019. 3 In response, the World Health Organization (WHO) launched the Global Diabetes Compact in 2021 aimed at sustaining improvements in diabetes prevention and care, through collaborative multidisciplinary initiatives with national and international bodies. 4Type 2 diabetes mellitus (T2DM) accounts for over 90% of cases and can be prevented or delayed. 2 Major clinical trials and reviews have established the effectiveness of diet and lifestyle modifications, and of metformin, in preventing T2DM among certain older, high-risk population groups. 5hile previously considered a transient condition, with no lasting adverse impact, gestational diabetes mellitus (GDM) is now a well-established risk factor for developing T2DM.In a most recent pooled analysis of 1.3 million women, women with prior GDM had a 10-fold risk of developing T2DM compared with women without GDM, identifying a key high-risk group. 6The prevalence of GDM in pregnancies varies markedly worldwide, ranging from 2% to 25%. 7 Importantly, the risk of developing T2DM appears to be particularly high in the first few years after childbirth, 6,8 and those diagnosed with diabetes below 40 years of age are found to have an increased risk of cardiovascular disease than those diagnosed later, which provides a compelling case for early intervention. 9 recent systematic review of randomized trials in lifestyle interventions found benefits in reducing the incidence of T2DM among 3745 participants. 10No previous systematic reviews have been undertaken of pharmacotherapeutic approaches, or of all intervention types, to examine the effects on diabetes prevention in women with recent GDM.However, a scoping review of pharmacological interventions in women with a history of GDM suggested metformin to be effective with limited interpretability of other drugs (thiazolidinediones, troglitazone, pioglitazone, and vildagliptin). 11Therefore, we undertook a systematic review and meta-analysis to assess the effectiveness of preventive interventions, of any type, to reduce the incidence of T2DM and biochemical markers in women with a recent history of GDM.Further analysis was conducted to examine the effect of specific intervention types.As several trials are in progress, [12][13][14][15][16] we propose to conduct annual surveillance for the next 5 years to maintain a living systematic review.

| METHODS
This study was conducted according to the 2015 Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P) statement.The study protocol was registered with the international database of prospectively registered systematic reviews in health and social care (PROSPERO-CRD42021279891). A detailed study protocol outlining the predefined eligibility criteria, search strategy, data analysis methods, and risk of bias assessment has been previously published. 17
The eligibility criteria for inclusion were as follows: (1) Evaluation: randomized controlled trials; (2) Population: women within 5 years of a pregnancy complicated by GDM; (3) Intervention and comparator: any type including lifestyle, behavioral, psychological, or pharmacotherapy compared with another active intervention, usual care, or placebo; (4) Outcomes: diagnosis of T2DM or a measure of dysglycemia; (5) Follow-up: minimum of 12 months.GDM was defined according to any recognized diagnostic criteria or based on medical record documentation.Where multiple publications of the same trial were present, the one with the longest available follow-up period was included.There were no language restrictions.The reference lists of eligible articles and previous reviews were also screened for relevant studies.The living status of the systematic review will be maintained for 5 years after the protocol publication (November 2021), 17 with an updated search in November 2024 and planned every 12 months thereafter.

| Screening and data extraction
Screening and data extraction were conducted independently by two authors (VL and MRM), and any disagreements were resolved by consensus with a third author (AP).The abstracts were screened against the inclusion and exclusion criteria, followed by the full text of potentially eligible trials.Data from eligible articles confirmed by the authors were extracted, risk-of-bias assessed, and template for intervention description and replication (TIDieR) checklist completed by VL and MRM.The non-English publications were screened and extracted by a native speaker who is a part of the research team (RL).Data were extracted using a standardized electronic template.Details of the extracted variables are presented in Data S1.

| Outcomes
The primary outcome was the incidence of T2DM, as defined by the individual study.Secondary outcomes included fasting plasma glucose levels, fasting insulin levels, HOMA-IR score, 2-h oral glucose tolerance test (OGTT), Haemoglobin A 1 c (HbA 1 c), body weight, body mass index, waist circumference, total cholesterol, highdensity lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides.

| Data analysis
The details of eligible studies were summarized.Study characteristics and available baseline participant data were described by measures of central tendency.Random-effects meta-analysis using the Hartung-Knapp-Sidik-Jonkman method were conducted to generate an overall effect estimate for each outcome measure.The pooled estimates of effect sizes were reported as risk ratios for binary outcomes and as mean differences for continuous outcomes.For the primary outcome of interest incidence of T2DM, the overall effect estimate was reported both as risk ratio (including studies that reported binary data) and as hazard ratio (including studies that reported hazard ratio and its measure of variability).Subgroup analyses were conducted according to (1) the type of intervention (lifestyle vs. pharmacological intervention); (2) average race-specific baseline body mass index (BMI) (obese vs. nonobese) 18 ; and (3) income classification of the study country per the World Bank (high-income vs. lowand middle-income).Sensitivity analyses, excluding high risk of bias studies, 14,19,20 and a suspected outlier 20 identified through leave-one-out meta-analysis, were conducted to check the robustness of the primary analysis results.
For continuous outcomes, postintervention and change-from-baseline data were combined in a single meta-analysis.Study-level estimates were converted to a common scale or unit before pooling (for example, fasting plasma glucose was converted to mmol/L if reported in other units of measurement).Standard errors (SE) and confidence intervals (CI) were converted to standard deviations (SD) using the equations outlined in the Cochrane Handbook. 21Medians and interquartile ranges were converted to means and SD using the methods proposed by Wan et al. 22 For cluster trials, clustering was taken into account by calculating the trial's effective sample size.An intraclass correlation coefficient of 0.01 was used to obtain the trial's design effect, and a common design effect was applied across treatment arms.
Quantitative heterogeneity was assessed by evaluating the proportion of variability due to heterogeneity through the I 2 statistic and by using the Cochran Q test of homogeneity.Presence of small-study effects was assessed by visual inspection of the contour-enhanced funnel plots and through regression-based Egger test.
Analyses were based on reported data based on the intention-to-treat principle.No missing data were imputed.Analyses were conducted using Stata version 17 (StataCorp LLC, College Station, TX, USA).

| Risk of bias assessment
A risk of bias assessment for each published trial was conducted in duplicate using the Cochrane risk-of-bias tool (RoB 2). 23Studies were classified into "low risk of bias," "unclear risk of bias" and "high risk of bias" using the RoB 2 tool by assessing several domains including random allocation sequence, allocation sequence concealment, blinding, outcome assessment, missing data, and analysis methods.

| Implementation assessment
The implementation of interventions was assessed using the TIDieR checklist and guide. 24

| RESULTS
A total of 3812 abstracts were identified by the search strategy, with 15 studies meeting the eligibility criteria.
Two further articles were identified through manual citation searches, and no duplicate reports of interventions were included.A total of 17 studies were included in this review (Figure 1).

| Publication bias and quality
The risk-of-bias summary is provided in Figure S1.Overall, 53% (n = 9) 28,29,[31][32][33][34][36][37][38] of the studies were rated as having a low risk of bias, 29% (n = 5) [25][26][27]30,35 as having an unclear risk of bias, and 18% (n = 3) [25][26][27]30,35 as having a high risk of bias. Two sudies were rated as having a high risk of bias due to the insufficient information in the publications, 19,39 and one due to a significant number of dropouts at the final follow-up (40% lost to followup).20 Studies rated as having unclear risk of bias [25][26][27]30,35 were mainly due to lack of information provided by the studies, especially of allocation sequence concealment (n = 1), 26 missingness of the data (n = 3), 25,30,35 and appropriate prespecified analysis plan (n = 1).37 The Egger test and the funnel plot for the 10 studies that report the incidence of T2DM suggest absence of publication bias (Figure S2; p = 0.38).The Egger test also suggests absence of publication bias for the secondary outcomes (p > 0.05) apart from BMI (p = 0.038), although the contour-enhanced funnel plot looks symmetrical.

| Outcomes
The pooled effects of the intervention, compared with control, on all outcomes are summarized in Table 2.

| Subgroup analyses
Subgroup analysis by the type of intervention, baseline BMI, and country income class are summarized in Table 3.There was no significant heterogeneity between subgroups, despite the effect size estimates potentially favoring greater benefit with pharmacological (n = 379; hazard ratio, 0.47; 95% CI: 0.27-0.82;F I G U R E 3 Primary outcome of the incidence of type 2 diabetes mellitus (hazard ratio).CI, confidence interval.
T A B L E 3 Subgroup analysis on the incidence of type 2 diabetes mellitus (T2DM).
No  F I G U R E 4 Subgroup analysis by type of intervention.CI, confidence interval.

| Sensitivity analysis
The sensitivity analysis excluding high risk of bias studies and the suspected outlier did not change the effect observed in most outcomes, apart from HOMA-IR and LDL cholesterol.Removal of Zilberman et al., 20 identified as the outlier and having a high risk of bias, shifted differences in HOMA-IR from being not significant (À0.56; 95% CI: À1.12 to À0.01; p = 0.05; I 2 = 96%) to significant (À0.

| DISCUSSION
The current review suggests equivocal findings with respect to the effects of interventions aimed at preventing T2DM among women with a recent history of GDM.
Overall, there was substantial heterogeneity between trials.Statistically significant benefits were identified only in a meta-analysis of four trials where survival analysis was used, with a wide 95% CI.Point estimates suggested that the benefits of pharmacological intervention may be greater than that of lifestyle strategies; however, the difference was not statistically significant.The limited number of pharmacotherapy studies highlights the need for further trials, of which three is currently underway. 12,13,40he current living systematic review planned annually for the next 5 years will provide up-to-date evidence of the effects as they emerge.This is the first review to include any type of intervention to reduce the risk of T2DM in women post-GDM.While our analyses suggest the possibility of a greater benefit with pharmacological compared with lifestyle interventions, the small number of studies limits our ability to draw firm conclusions.Similarly, the most recent scoping review of pharmacological interventions in this population highlighted the need for further pharmacological studies. 11ne pharmacological study included in this review was terminated prematurely due to hepatotoxicity concerns and the drug, troglitazone, has been withdrawn for use. 23Therefore, only two trials to date are of clinical relevance.A search of the Clinical Trial Registries shows three studies 12,13,40 in progress that are evaluating the effects of liraglutide and semaglutide on incidence of T2DM in women post-GDM.While the results of these studies will provide further evidence on the effects of pharmacological interventions, the relatively small sample sizes (n = 80-206) indicate a need for large robust trials to provide definitive data.
Approaches to modify lifestyle intervention were the most common intervention type evaluated, and we found equivocal evidence that these interventions reduced the risk of T2DM in women with a history of GDM.Efficacy of lifestyle intervention depends heavily on adherence to intervention, and several factors are found to influence this including having reputable intervention facilitators, providing personalized guidance, and supervised sessions. 41hile interventions in all but one study were provided by reputable intervention facilitators, only 50% of the physical activity and 61% of diet interventions were personalized, with only two studies providing supervised sessions.Furthermore, only two studies reported adherence to intervention, which was relatively low with reports of 34% attending at least one walking session and 58.3% attending 50% or more of the provided sessions.Although retention rate for most of the studies were high, adherence to intervention is unknown, which is of concern as adherence to intervention is especially problematic in this population. 42herefore, reporting of adherence to intervention components (to the extent feasible) is strongly recommended in future intervention studies in postpartum women.
Unlike the current review, a recently published lifestyle interventions post-GDM found interventions to be associated with significant reductions in the risk of developing T2DM. 10 This review included intervention delivered at any time following pregnancy affected by GDM while we focused only on interventions delivered relatively early in the postpartum period.We thus excluded the subgroup analysis of the Diabetes Prevention Program 43 where both lifestyle and metformin were found to be beneficial in a subset of women (n = 350) with a history of GDM (average 656 weeks postpartum). 43It is uncertain whether such benefits observed in an older cohort more distant to their index pregnancy would extend to interventions delivered in the early postpartum period.Furthermore, our review only included studies with at least 12 months follow-up to reduce the likelihood of chance findings.For example, the review by Ratnakaran et al. 10 included a study with a duration of 4 months, which showed a significant benefit with the lifestyle intervention. 44Therefore, we believe the current review that focuses on intervention delivered early postpartum, and with a follow-up of at least 12 months in duration, report findings that are robust and specific to women with a recent history of GDM. 45 Furthermore, this may explain why the current review found no significant improvements in anthropometric measures but did in fasting glucose and insulin levels different to other systematic reviews. 45,46This is also the first review to analyze changes to lipid profiles and to show reductions in LDL cholesterol.However, this shifted significance when a sensitivity analysis was conducted by excluding a study with high-risk of bias.The sensitivity analysis also shifted the significance of HOMA-IR from not significant to significant, suggesting improvements in the intervention group compared with controls.These benefits would be favorable long-term; however, the current review with a median follow-up of 24 months may not have been long enough to capture this translation into reductions in T2DM.Therefore, although the evidence of the effects suggests a benefit, the small number of trials and participants and the short follow-up period limit our ability to make firm conclusions.
The current review specified clear criteria to try and identify effectiveness of preventive interventions, of at least 12 months in duration, on reducing the risk of T2DM in women with a recent history of GDM.While this allowed us to answer our proposed question, it limited the number of included studies.Furthermore, combining different types of intervention resulted in large heterogeneity of the outcomes.However, by combining the different intervention types, the current review identified the need for more adequately powered pharmacotherapy interventions to examine its efficacy.

| CONCLUSION
This review indicates that the benefits of preventive interventions to reduce the risk of T2DM in women post-GDM when initiated within 5 years postpartum remain equivocal.While there is little debate that improving diet and physical activity, and other changes to lifestyle, can prevent T2DM, sustainable and scalable strategies to effectively achieve such changes in this population remain uncertain.Pharmacological approaches show promise, but the evidence is sparse.This living systematic review for the next 5 years will provide updated evidence on preventive interventions.

F I G U R E 2
Primary outcome of the incidence of type 2 diabetes mellitus (risk ratio).CI, confidence interval.
Abbreviation: CI, confidence interval.a Categorized according to race specific body mass index (BMI).
Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) diagram.Characteristics of eligible studies and participants.
T A B L E 1Note: $ denotes proposed follow-up period, which changed if individuals were diagnosed with diabetes.Abbreviations: ADA, American Diabetes Association; ADIPS, Australasian Diabetes in Pregnancy Society; GDM, gestational diabetes mellitus; IADPSG, International Association of Diabetes and Pregnancy Study Groups; n/a, not avai; T2DM, type 2 diabetes mellitus; WHO, World Health Organization; HbA Pooled estimates of intervention effects on outcomes.